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2006 Grant - Cryns

Molecular Interactors for Alpha-Secretase: Physiopathological Role

Vincent Cryns, M.D.Northwestern University Feinberg School of MedicineChicago, Illinois

2006 Investigator-Initiated Research Grant

Two characteristic features of Alzheimer pathology are amyloid plaques and neurofibrillary tangles. Amyloid plaques exist outside of nerve cells and consist primarily of beta-amyloid protein fragments. Neurofibrillary tangles exist within nerve cells and consist of tangles of the protein tau. Amyloid plaques and neurofibrillary tangles were once considered unrelated, but recent studies have shown complex connections between these features.

Vincent Cryns, M.D., and colleagues found that when neurons were exposed to beta-amyloid, a class of proteins called caspases was activated. These caspases then cut the tau proteins into a form that enables them to assemble into neurofibrillary tangles.

Although these findings were intriguing, they left several unanswered questions that the researchers will now address. For example, previous research was conducted using cultured nerve cells, so it is still unknown whether amyloid activation of caspases and the subsequent cutting of tau occurs in the brains of living animals. A second important question is whether this process leads to, or contributes to, the eventual death of nerve cells.

These questions will be addressed by using a combination of techniques in cultured cells and animal models. The researchers will cause nerve cells to express tau that is either resistant to the cutting action of caspases or that is already cut at the same location. They will then observe how these changes affect the nerve cells. Findings from this study may shed light on the complex interplay between the pathological features of Alzheimer's disease.